Bone is continuously remodeled throughout life, with complete skeletal turnover estimated to occur every decade in humans. The osteoclast is a key cell in homeostatic bone remodeling, but excess osteoclast activity leads to bone pathology, including the highly prevalent disease osteoporosis. In rheumatoid arthritis, the inflammatory environment activates osteoclasts, resulting in bone erosions and generalized bone loss. While the signaling pathways, transcription factors and molecular machinery that govern osteoclast differentiation and resorptive activity have been studied intensively over the past two decades, much less is understood about the generation, migration and commitment of OC precursor cells (OCP). In this grant we seek to expand our understanding of OCP function and trafficking in homeostatic and inflammatory bone remodeling in vivo. We have recently identified a bone marrow CD11b-/lo Ly6Chi population with ex vivo osteoclast precursor (OCP) activity. The experiments we propose will establish whether bone marrow CD11b-/lo Ly6Chi OCP are multi-potent myeloid precursors or are restricted to the osteoclast lineage in vivo. Building on this we will determine if inflammation induces cell intrinsic changes in the OCP that alter its progenitor properties and examine the requirements for OCP to traffic to inflamed joints. To establish whether mouse models investigating OCP can be applied to understanding human OCP, we propose to define the human bone marrow osteoclast precursor. This grant will advance our basic understanding of the osteoclast lineage in mice and humans, and contribute to knowledge about skeletal remodeling and joint destruction in inflammatory arthritis. We anticipate our data will be directly applicable to understanding bone destruction in RA, osteoporosis and related inflammatory diseases.